ZA200404628B - HIV integrase inhibitors. - Google Patents

HIV integrase inhibitors. Download PDF

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Publication number
ZA200404628B
ZA200404628B ZA200404628A ZA200404628A ZA200404628B ZA 200404628 B ZA200404628 B ZA 200404628B ZA 200404628 A ZA200404628 A ZA 200404628A ZA 200404628 A ZA200404628 A ZA 200404628A ZA 200404628 B ZA200404628 B ZA 200404628B
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Prior art keywords
alkyl
aryl
compound
heteroaryl
pharmaceutically acceptable
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ZA200404628A
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Michael A Walker
Roger Remillard
Jacques Banville
Serge Plamondon
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Bristol Myers Squibb Co
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Description

® -
HIV INTEGRASE INHIBITORS h
Background ) I tL Cl }
Human immunodeficiency virus (HIV) has been identified as the etiological agent responsible for acquired immune deficiency syndrome (AIDS), a fatal disease characterized by destruction of the immune system and the inability to fight off life threatening opportunistic infections.
Recent statistics (UNAIDS: Report on the Global HIV / AIDS Epidemic,
December 1998), indicate that as many as 33 million people worldwide are infected with the virus. In addition to the large number of individuals already infected, the virus continues to spread. Estimates from 1998 point to close to 6 million new infections in that year alone. In the same year there were approximately 2.5 million deaths associated with HIV and
AIDS.
There are currently a number of antiviral drugs available to combat the infection. These drugs can be divided into three classes based on the viral protein they target and their mode of action. In particular, saquinavir, indinavir, ritonavir, nelfinavir and amprenavir are competitive inhibitors of the aspartyl protease expressed by HIV.
Zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavir are nucleoside reverse transcriptase inhibitors that behave as substrate mimics to halt viral cDNA synthesis. The non-nucleoside reverse transcriptase inhibitors, nevaripine, delavaridine and efavirenz inhibit the synthesis of viral cDNA via a non-competitive (or uncompetitive) :
2 ® mechanism. Used alone these drugs are effective in reducing viral replication. The effect is only temporary as the virus readily develops resistance to all known agents. However, combination therapy has proven very effective at both reducing virus and suppressing the emergence of resistance in a number of patients. In the US, where combination therapy is widely available, the number of HIV-related deaths has declined (Palella, F. J.; Delany, K. M.; Moorman, A. C;
Loveless, M. O.; Furher, J.; Satten, G. A.; Aschman, D. J.; Holmberg, S. D.
N. Engl. J. Med. 1998, 338, 853).
Unfortunately, not all patients are responsive and a large number fail this therapy. In fact, approximately 30-50% of patients ultimately fail combination therapy. Treatment failure in most cases is caused by the emergence of viral resistance. Viral resistance in turn is caused by the rapid turnover of HIV-1 during the course of infection combined with a high viral mutation rate. Under these circumstances incomplete viral suppression caused by insufficient drug potency, poor compliance to the complicated drug regiment as well as intrinsic pharmacological barriers to exposure provides fertile ground for resistance to emerge. More oo disturbing are recent findings which suggest that low-level replication continues even when viral plasma levels have dropped below detectable levels (< 50 copies/ml) (Carpenter, C. C.J.; Cooper, D. A.; Fisch], M. A;
Gatell, J. M.; Gazzard, B. G.; Hammer, S. M.; Hirsch, M. 5.; Jacobsen, D.
M.; Katzenstein, D. A.; Montaner, J. S.; Richman, D. D.; Saag, M. 5.;
Schecter, M.; Schoolery, R. T.; Thompson, M. A; Vella, S;; Yeni, P. G.;
Volberding, P. A. JAMA 2000, 283, 381). Clearly there is a need for new antiviral agents, preferably targeting other viral enzymes to reduce the rate of resistance and suppress viral replication even further. Co
HIV expresses three enzymes, reverse transcriptase, an aspartyl protease and integrase, all of which are potential antiviral targets for the
B 30 development of drugs for the treatment of AIDS. However, integrase
® | 3 stands out as being the only viral enzyme not targeted by current therapy.
The integrase enzyme is responsible for insertion of the viral cDNA into the host cell genome, which is a critical step in the viral life cycle. There are a number of discrete steps involved in this process including : processing of the viral cDNA by removal of two bases from each 3'- terminus and joining of the recessed ends to the host DNA. Studies have shown that in the absence of a functional integrase enzyme HIV is not infectious. Therefore, an inhibitor of integrase would be useful as a therapy for AIDS and HIV infection.
A number of inhibitors of the enzyme have been reported. These include, nucleotide-based inhibitors, known DNA binders, catechols and hydrazide containing derivatives (Neamati, N.; Sunder, S.; Pommier, Y.,
Drug Disc. Today, 1997, 2, 487). However, no clinically active compound has resulted from these leads. Thus, what is needed is a clinically effective inhibitor of the HIV integrase enzyme.
Summary of Invention
The present invention relates to compounds of Formula I, or pharmaceutically acceptable salts or solvates thereof.
Ri-~nB
Op : Formula I
In Formula],
Rlis : : -aryl, -C1-Cs alkyl-aryl, -C1-Cs alkyl-5(O)n-aryl, -C1-Cs alkyl-O-aryl; or wherein R! is unsubstituted or substituted with 1-3 R3;
Cy ®
Each R3 is independently selected from
H, -halo, -CN, -C1-Ce alkyl, -C3-Cs cycloalkyl -OR¢, -C1-Cyo alkyl-O-R¢, -CO4R5, -C1-Cro alkyl-CO2RS, -N(RS)(R?), -C1-Cyo alkyl-N(R$)(R?), -CON(RSKR?), -C1-C1o alkyl-CON(RS)(R?) -S(O)nRE, -C1-Cao alkyl-S(O)qR8 oo -S(O)NR?)RY), ~C1-Cro alkyl-S(O)aN(R?) (R19), -aryl, -O-aryl, -heteroaryl, } -O-heteroaryl, -C1-Cs alkyl-aryl, -C1-Cs alkyl-heteroaryl, -C(O)-heterocyclic radical, | oo -C1-Cyo alkyl-C(O)-heterocyclic radical, or -C1-Cs haloakyl; oo
R2is : -H, - 30 -Ci-Cyp alkyl,
® 5 -C3-Cs cycloakyl, -C1-Cyo haloalkyl, -aryl, -heteroaryl, -C1-Cs alkyl-aryl, -C1-Cs alkyl-O-ary], -C1-Cs alkyl-heteroaryl, -C-Cs alkyl-O-heteroary], -C1-Cioalkyl-OR¢, -C1-Cyo alkyl-CO2RS, -C1-Cro alkyl-N(RS)(R?), -C1-Cio alkyl-CON(RE)(R7), -C1-Cyo alkyl-S(O)qRS, -C1-Cyo alkyl-S(0).N(R?) (RY), or -C1-Co alkyl-C(O)-heterocyclic radical;
Each R*is independently selected from
H, -C1-Ce alkyl, -C3-Cs cycloalkyl, -C1-Co alkyl-CO;RS, -C1-Cy alkyl-N(R6)(R?), -C1-Co alkyl-CON(RS)(R), . -C1-Co alkyl-S(O)qR8, or -C1-Cs alkyl-S(O)aN(R9)(R10); . 25 Each R°is independently selected from -H, : -C1-Ce alkyl, -C3-Cs cycloalkyl, or : -C1-Cs alkyl-aryl;
Each Ris independently selected from
} ® -H, -C1-Cs alkyl, -aryl, -heteroaryl, -C1-Ce alkyl-aryl, -C1-Cs alkyl-heteroary], -C(0)-C1-Ce alkyl, -C(O)-aryl, -C(0)-C1-Cs alkyl-aryl, -C(O)-heteroaryl, -C(0)-C1-Cs alkyl-heteroaryl, -C(NH)NH,, -5(O)n-R8, or -C1-Ce alkyl-CO2RS;
Each R’is independently selected from -H, -C1-Ce alkyl, -aryl, or -heteroaryl;
Each R8is independently selected from -C1-Cs alkyl, -aryl, or -heteroaryl;
Each R? is independently selected from -H, . -C1-Ce alkyl, -Cy-Cs alkyl-aryl, oo -C1-C¢ alkyl-heteroaryl, -C(0)-C1-Cs alkyl, - 30 -C(O)-aryl,
° , -C(0)-Ci-Cs alkyl-aryl, } -C(O)-heteroaryl, -C(0)-C1-Cs alkyl-heteroaryl, -aryl, or : -heteroaryl;
Each R¥ is independently selected from : -H, -C1-Ce alkyl, -C1-Ce alkyl-aryl, -C1-Cs alkyl-heteroaryl, -aryl, or -heteroaryl;
RU ig
H, -aryl, -heteroaryl, -C3-Cs cycloalkyl, -C1-Cs alkyl, -C1-Cs alkyl-aryl, -C1-GCs alkyl-heteroaryl, -C1-Cs alkyl-CO2RS, or -C1-Cs alkyl-N(R6)(R7);
R2js -H, -C1-Ce alkyl, -aryl, or -heteroaryl;
RB ig -H, -C1-Cs alkyl,
( : ; ® -aryl, or -heteroaryl;
Bl is selected from the group consisting of
O OH 0 O a NAN Ong wn AAO pt 0 , © , 12 oH 9 0 ok wr se Og WAAC o , or 0 ; and nis0,1or2.
The present invention also relates to a method of inhibiting HIV integrase by administering to a patient an effective amount of a compound of Structural Formula Ia, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
Nr 5 re
Formula Ia
In Formula Ia, R3, R?, R3, R4, R5, Ré, R7, R8, R? and R19 are as defined for Formula I, whereas B2 is
O OH 0 0 OH O “ AA oH sn AN oH ANA o o! or o
Cl
The present invention further relates to a method of treating patients infected by the HIV virus, or of treating AIDS or ARC, by - administering to the patient an effective amount of a compound of
® 9
Structural Formula Ia, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
Another embodiment includes a pharmaceutical composition, useful for inhibiting HIV integrase, or for treating patients infected with the HIV virus, or suffering from AIDS or ARC, which comprises a therapeutically effective amount of one or more of the compounds of
Formula Ia, including pharmaceutically acceptable salts, solvates or prodrugs thereof, and a pharmaceutically acceptable carrier.
Detailed Description of the Invention oo
In the present invention, unless otherwise specified the following definitions apply. :
The numbers in the subscript after the symbol “C” define the number of carbon atoms a particular group can contain. For example, “Ci-C¢” means a substituent containing from one to six carbon atoms.
As used herein, the term “alkyl” means a saturated, straight chain or branched monovalent hydrocarbon radical having the stated number of carbon atoms. Examples of such alkyl radicals include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and, where indicated, higher homologs and isomers such as n-pentyl, n-hexyl, 2- methylpentyl and the like. Haloalkyl refers to an alkyl radical that is substituted with one or more halo radicals, such as trifluoromethyl.
As used herein, the term “cycloalkyl” means a non-aromatic 3-6 membered ring. Examples include, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Halo means chloro, bromo, iodo or fluoro. ) “Aryl” means an aromatic hydrocarbon having from six to fourteen carbon atoms; examples include phenyl and napthyl, indenyl, azulenyl, fluorenyl and anthracenyl.
10 ®
The term “heterocyclic radical” refers to radicals derived from monocyclic saturated heterocyclic nuclei having 3-6 atoms containing 1-3 heteroatoms selected from nitrogen, oxygen or sulfur. Heterocyclic radicals include, for example, piperidinyl, piperazinyl, pyrrolidinyl and morpholinyl. “Heteroaryl” means a five- or six-membered aromatic ring containing at least one and up to four non-carbon atoms selected from oxygen, sulfur and nitrogen. Examples of heteroaryl include 2-furyl, 3- furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, 2-thienyl, 3-thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3 4-thiadiazolyl, pyridazinyl, pyrimidinyl, 1,3,5-triazinyl and 1,3,5-trithianyl.
In a preferred embodiment, compounds of the present invention that are useful for treating AIDS have the structure of Formula II.
AISNE
Org
Formula II
In Formula II, R}, R2, RS, R%, R5, R¢, R7, R8, R? and RY are as defined for Formula I, while B2 is defined as in Formula Ia.
In yet another embodiment of the present invention, compounds having the structure of Formula II], as follows, are preferred chemical intermediates from which compounds, or pharmaceutically acceptable salts, solvates or prodrugs, useful for the treatment of AIDS are formed.
Even more preferentially, the compounds of Formula IIT are useful, oo themselves, as prodrugs and can be administered as a prodrug to a patient as a compound or in pharmaceutical formulation.
® n
RZ _13 0 ox a ( bp ©
Formula III
In Formula ITI, R?, R?, R3, R%, R5, RS, R7, R8, R?, R10, R12 and R12 are as defined for Formula I.
In a more preferred embodiment, compounds of the present invention have the structure of Formula IV, shown below hea NE
R14 SNE rR
Formula IV wherein:
Each R1* is independently selected from -CN, -H, or halo;
RBs ~~ -CH,C(O)N(CHs): or -C1-Cz alkyl; and
B? is as defined for Formula Ia.
By virtue of its acidic moiety, where applicable, a compound of
Formula I forms salts by the addition of a pharmaceutically acceptable base. Such base addition salts include those derived from inorganic bases which include, for example, alkali metal salts (e.g. sodium and potassium), alkaline earth metal salts (e.g. calcium and magnesium), aluminum salts and ammonium salts. In addition, suitable base addition

Claims (26)

118 ® We claim:
1. A compound of formula I rR!” ON” 8’ \ 0-p2 1 wherein Rlis : -aryl, ~ -C3-Cs alkyl-aryl, -C3-Cs alkyl-5(O)n-aryl, or -C1-Cs alkyl-O-aryl; and wherein R! is unsubstituted or independently substituted with 1-3 R3; Each R2 is independently selected from “H, -halo, -CN, -C1-Cs alkyl, -C3-Cs cycloalkyl -OR¢, -Ci-Cio alkyl-O-R%, -CO2R>, -C1-Cyo alkyl-CO2R5, -NRE)(R?), -C1-Cyo alkyl-N(RE)R?), oO -CON(RS)(R?), -C1-Co alkyl-CON(RE)(R?) -S(O)nRS, -C3-Cao alkyl-S(O)aRS,
® 119 : -5(0)aN(R%) (RY), -C3-Cyo alkyl-5(0)N(R?)(R19), -aryl, -O-aryl, -heteroaryl, : -O-heteroaryl, -C1-Ce alkyl-aryl, ~C1-Cs alkyl-heteroaryl, -C(O)-heterocyclic radical, -C3-Cyo alkyl-C(O)-heterocyclic radical, or -C1-Cshaloakyl; R2is
. -H . -C1-Cyo alkyl, -C35-Cs cycloakyl, - -C1-Cp haloalkyl, -aryl, heteroaryl, _C1-Cs alkyl-aryl,20 -Ci-Gs alkyl-O-aryl, -C1-Cs alkyl-heteroaryl, -C1-Cs alkyl-O-heteroaryl, -C1-Cro alkyl-OR4, -C1-Cyo alkyl-CO2R3, -C1-Crpalkyl-N(RS)(R?), -C1-Cio alkyl-CON(RS)(R7), -C1-Cro alkyl-S(O)nR8, oo _C1-Cro alkyl-S(O)-N(R) (RI), or ~C1-Cuo alkyl-C(O)-heterocydlic radical; Each R¢is independently selected from
120 ® H, -C1-Cg alkyl, -C3-Cs cycloalkyl, -C1-Cy alkyl-CO2RS5, -C3-Co alkyl-N(R6)(R?), -C1-Co alkyl-CON(RS)(R?), -C1-Cy alkyl-5(O)nR8, or -C1-Cy alkyl-S(O)aN(R?)(R10); Each R5 is independently selected from -H, -C1-Cs alkyl, -C3-Cs cycloalkyl, or -C1-Cs alkyl-aryl; " Each Réis independently selected from -H, -C1-Cg alkyl, -aryl, -heteroaryl, -C1-Cg alkyl-aryl, -Cy-Cg alkyl-heteroaryl, -C(O)-C1-Cs alkyl, -C(O)-aryl, -C(0)-C1-Cs alkyl-aryl, -C(O)-heteroaryl, -C(O)-C1-Cs alkyl-heteroaryl, -C(NH)NH, -S(O)«-R?, or - -C1-Cs alkyl-CO2RS; Each R7? is independently selected from — oo ; L :
® 121 -C1-Cs alkyl, -aryl, or -heteroaryl; Each R8 is independently selected from CC alkyl, : | -aryl, or heteroaryl; Each R? is independently selected from } -H, -C;-GCs alkyl, -C1-Cs alkyl-aryl, , ~C1-C alkyl-heteroaryl, -C(0)-C1-Cs alkyl, -C(O)-aryl, -C(O)-Ci-Cs alkyl-aryl, -C(O)-C1-Cs alkyl-heteroaryl, -aryl, or -heteroaryl; Each R10 is independently selected from -H, -C1-Cs alkyl, -C1-Cs alkyl-aryl, -C;1-Cs alkyl-heteroaryl, -aryl, or -heteroaryl; : Rll is -H, -aryl, -heteroary], -Ci1-Cs alkyl-heteroaryl,
{ { 122 ® -C3-Cs cycloalkyl, -C1-Ce alkyl, -C1-C alkyl-aryl, -C1-Cs alkyl-CO2R5, or -Ci-Ce alkyl-N(RE)(R?); R12is H, -C1-Cs alkyl, -aryl, or -heteroaryl; RB is H, -C1-Cs alkyl, -aryl, or heteroaryl; and R12 and R® taken together may form a cyclic alkyl ketal; Bl is selected from the group consisting of O OH oO O sO Ri a O , © , 12 on 0 0 ok SNA oe LP 0) , or O ; and nis0,1or2; or a pharmaceutically acceptable salt or solvate thereof. oo
2. A compound of Claim 1 wherein
C 123 Riis -phenyl or -Ci-C; alkyl-phenyl wherein the phenyl is unsubstituted or independently substituted with 1-3 R3; Each R? is independently selected from -H oo -halo, -CN, -C1-Cealkyl, -OC1-Cealkyl, -COzRs, NER(R?), -CON(R®)(R?), -trifluoromethyl; R?is -Ci-Cealkyl, -CHz-phenyl, -CH2-CO2R?, “C1-Ca-alkyl-N(R6)(R7), -CH2-CON(RS)(R7), : -CH2-C(O)-heterocyclic radical; R1 is R5; R*? and R13 are C;-Cs alkyl or can be taken together may form a cyclic alkyl ketal; : Bl is selected from the group consisting of
O OH 0 O SANA Og 1 AAO 1 0 , 0 ,
JUL. 2.2883 1:48PM BM" PATENT 203 677 6920 NO.946 P.9 0 Y. f CT-2695-PCT ER TE Ch WL EAS 52 JUL 2003 @® 124 P R OH O o oX 0 oO SAN ~ RY Lo o ’ or NI . .
3. A compound of claim 1 wherein Riis R14 ne oo R14 ‘ o in which R¥, R1¢' and Ri" are each independently selected from cyano, hydrogen or halo; R? is C1-C; alkyl or -CH2C(O)N(CHa)q; and Bl is O OH oO O OH © a wo ANA or | o o or co .
4. A compound of claim 3 selected f cm the group consisting of: 3-{(4Fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid; 3-1(34-Difluoro-benzyl)-methoxy-carbamoyl}-2-hydroxy-acrylic acid; 3-(3-Bromo-4-fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid; 3-(3-Cyano-4-fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid; 3-{(4-Fluoro-3-methyl-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid; 3-[Ethoxy~(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic acid.
5. A compound of the formula : AMENDED QUEET
C 125 0 OH
OE . OCH; or a pharmaceutically acceptable salt or solvate thereof.
6. A compound of the formula Oo OH jeg aa r OCH; S cl or a pharmaceutically acceptable salt or solvate thereof.
7. A compound of the formula : 0] OH Ione. E OCH; F or a pharmaceutically acceptable salt or solvate thereof.
8. A compound of the formula 0 OH eg aa. E OCH3 Br or a pharmaceutically acceptable salt or solvate thereof.
9. A compound of the formula
JUL. 2.2883 1:48PM BM CATENT 203 677.6908 NO.946 P.108 v a A BEE Re et EWR Re “PEAS gy JUL 2003 PS CT-2695-PCT EA 126 O OH AL F OCHa CN : or a pharmaceutically acceptable salt or solvate thereof.
10. A compound of the formula O OH - Io SN
F i. : or a pharmaceutically acceptable salt or solvate thereof. : -
11. A compound of the formula 0 OH ~ JOR veo F Bk oo 0” NT oo or a pharmaceutically acceptable salt or solvate thereof. : 12. A compound of claim 1 wherein Riis : Ri4" ne oF R14 AMENDED Queer o 127 in which R™, R1¥ and R¥" are each independently selected from cyano, hydrogen or halo; R2is C1-Cz alkyl or -CH>C(O)N(CHs)y; and Blis R
12 ALT ” 0 in which R12 and R® are each independently C1-Cs alkyl or taken together form a cyclic alkyl ketal.
13. A compound of claim 12 wherein R12 and R33 are methyl.
14. A compound of claim 13 selected from the group consisting of: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N- methoxy-acetamide; N-(3,4-Difluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N- methoxy-acetamide; N-(3-Bromo-4-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo0-[1,3]dioxolan-4- ylidene)-N-methoxy-acetamide; N-(3-Cyano-4-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-{1,3]dioxolan-4- ylidene)-N-methoxy-acetamide; 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-Fluoro-3-methyl- benzyl)-N-methoxy-acetamide; 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-ethoxy-N-(4-fluoro- - benzyl)-acetamide.
15. A compound of the formula
; PCT/US02/39092 0 0 jh. OCH; 0 or a pharmaceutically acceptable salt or solvate thereof. oo
16. A composition useful for treating HIV infections comprising a : therapeutic amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
17. A pharmaceutical composition of claim 16, further comprising a therapeutically effective amount of one or more other HIV treatment agents selected from : (a) an HIV protease inhibitor, : (b) a nucleoside reverse transcriptase inhibitor, (c) a non-nucleoside reverse transcriptase inhibitor, (d) an HIV-entry inhibitor; (e) an immunomodulator, or a combination thereof. oo -
18. Use of a compound of Claim 1, or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for inhibiting HIV integrase.
19. Use of a compound of Claim 1, or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for treating an HIV infection in a patient in need thereof. AMENDED SHEET
‘ | PCT/US02/39092
20. A substance or composition for use in a method of inhibiting HIV integrase, said substance or composition comprising a compound of Claim 1, or a pharmaceutically acceptable salt or solvate thereof, and said method comprising administering a therapeutically effective amount of said substance or composition to a mammal in need of such treatment.
21. A substance or composition for use in a method for treating an HIV : infection in a patient in need thereof, said substance or composition comprising a compound of Claim 1, or a pharmaceutically acceptable salt or solvate thereof, and said method comprising administering a therapeutically effective amount of said substance or composition to such - patient, oo
22. A compound according to any one of claims 1, or 5 to 12, or 15, substantially as herein described and illustrated.
23. A composition according to claim 16, substantially as herein oo : described and illustrated.
24. A substance or composition for use in a method of treatment : according to any one of claims 16, or 20 or 21, substantially as herein I ~ described and illustrated.
25. Use according to claim 18, or claim 19, substantially as herem described and illustrated.
26. A new compound, a new composition, a substance or composition for a new use in a method or treatment, or a new use of a compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, substantially as herein described. AMENDED SHEET
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